Therapeutic methods designed to attenuate maladaptive emotional memories are not very efficacious. Disrupting the reconsolidation process has been proposed as a method to attenuate strong memories in psychopathologies such as PTSD, thereby reducing symptomology. Numerous studies, however, indicate that strong memories are resistant to becoming destabilized following reactivation, rendering them impervious to agents intended to block the re-stabilization phase of reconsolidation. Because of this, viable treatments to therapeutically attenuate maladaptive memories by taking advantage of the phenomenon of reconsolidation updating have yet to be fully developed. Our preliminary data indicate that it is possible to enhance the destabilization of strong memories by manipulating BLA NMDAR subunit composition. Here, we propose experiments to shed further light on the basic mechanisms of destabilization. We then propose experiments leveraging these insights to begin to develop translatable methods to modify previously unmodifiable fear memories. Aim 1: Our preliminary data indicate that increasing synaptic GluN2B levels in the mouse BLA enhances the initiation of reconsolidation of a strong fear memory. To produce these data, we generated lenti viruses to express GluN2B(E1479Q) within ?-CaMKII positive excitatory BLA neurons in a doxycycline-dependent manner. This system allows us to increase synaptic/surface expression of GluN2B after a strong fear memory has consolidated by inhibiting phosphorylation-driven endocytosis. We wish to extend these findings by using engram tagging technology to test the hypothesis that increasing synaptic GluN2B levels, specifically in the neurons making up the memory trace, is sufficient to enhance the initiation of reconsolidation of a strong fear memory. Aim 2: Simvastatin (SV), an FDA-approved medication, has been reported to enhance surface trafficking of GluN2B. Like our GluN2B(E1479Q) experiment, our preliminary data show that 5 days of SV treatment prior to fear memory retrieval enhances the induction of reconsolidation of a strong fear memory. Therefore, we propose to assess the ability of SV to enhance the initiation of reconsolidation of a strong fear memory by using an animal model of PTSD in conjunction with FDA-approved reconsolidation disruptors. Aim 3: In this aim, we will attempt to uncover the mechanism by which SV exerts its effect on the modifiability of strong fear memories. Critically, our GluN2B(E1479Q) and SV reconsolidation experiments converge on synaptic localization of GluN2B as a regulator of the modifiability of strong fear memories, but other preliminary data indicate that enhancing glutamatergic signaling to BLA pyramidal neurons may be critical for unlocking strong fear memories. Therefore, we propose a suite of biochemical and electrophysiological analyses to determine how SV alters BLA neuroplasticity. Together, the proposed studies will yield insights about the basic mechanisms of memory destabilization, aid in the development of methods to intervene on modification-resistant memories, and test potential clinical treatments to render traumatic memories modifiable in an effort to improve patient health.